This case is related to U.S. Pat. No. 5,519,021 and allowed application Ser. No. 450,330 filed May 5, 1995.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; ADS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of ADS and similar diseases, e.g., azidothymidine or AZT.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)].
Applicants demonstrate a substantially improved synthesis of an inhibitor of HIV reverse transcriptase, of the structure ##STR1## named (-)6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benz oxazin-2-one, hereinafter "Compound A." This compound is highly potent, even against HIV reverse transcriptase resistant to other AIDS antiviral compounds.
Applicants have devised a substantially improved synthesis of cyclopropylacetylene, an intermediate of Compound A. Prior methods employed two step procedures using corrosive reagents, and proceeded in low overall yield. See, for example, Militzer, H. C. et al., Synthesis, 998 (1993); Schoberth, W. et al., Synthesis, 703 (1972) [PCl.sub.5 and base]; Sherrod, et al., J. Am. Chem. Soc., 93:8, 1925-1940 (April, 1971) [I.sub.2 on the hydrazone]; Mikhailov and Bronovitskaya, Zh. Obshch. Khim., Vol. XXII, 195-201 (1952) [dibromide]. In contrast, the present process is shorter than prior methods, does not use corrosive reagents, and affords an overall yield as good or better than prior methods. The present process involves cyclization of 5-halo-1-pentyne in strong base.
Applicants have discovered that the successful outcome of this reaction requires generation of a transient dianion that cyclizes to cyclopropyl acetylene. No methods of the art generate a dianion. To the contrary, the art indicates that a variety of side reactions should occur, including chlorine displacement by the base or deprotonated acetylene, or halogen metal exchange of the chloride.